Journal
JOURNAL OF VIROLOGY
Volume 90, Issue 21, Pages 9841-9854Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01152-16
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Funding
- UK Medical Research Council [G0800312]
- MRC [MR/J008184/1]
- Wellcome Trust [108079/Z/15/Z]
- UCL/MRC Centre for Medical Molecular Virology Ph.D. studentship
- Medical Research Council [MR/J008184/1] Funding Source: researchfish
- Wellcome Trust [108079/Z/15/Z] Funding Source: researchfish
- Wellcome Trust [108079/Z/15/Z] Funding Source: Wellcome Trust
- MRC [MR/J008184/1] Funding Source: UKRI
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HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined. Here, we use a reductionist bead-coupled antibody assay as a model of the VS and show that cross-linking the integrin LFA-1 alone is sufficient to induce active T cell polarization and recruitment of the microtubule organizing center (MTOC) in HIV-1-infected cells. Mutant cell lines coupled with inhibitors demonstrated that LFA-1-induced polarization was dependent on the T cell kinase ZAP70. Notably, immunofluorescent staining of viral proteins revealed an accumulation of surface Env at sites of LFA-1 engagement, with intracellular Env localized to a Golgi compartment proximal to the polarized MTOC. Furthermore, blocking LFA-1-induced MTOC polarization through ZAP70 inhibition prevented intracellular Env polarization. Taken together, these data reveal that LFA-1 is a key determinant in inducing dynamic T cell remodeling to the VS and suggest a model in which LFA-1 engagement triggers active polarization of the MTOC and the associated Env-containing secretory apparatus to sites of cell-cell contact to support polarized viral assembly and egress for efficient cell-cell spread.
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